The clinical application of PDT encompasses a large parameter space with multiple variables. In understanding and optimizing efficacy and selectivity, we hypothesize that these factors often are limited by irradiance-dependent photodynamic oxygen depletion. We also hypothesize that non-invasive measurements ofphotobleaching kinetics and hemoglobin absorbance can yield important, real-time information about PDT; that host inflammatory/immune responses will be affected both by irradiance and fluence, and that DMXAA, an inducer of TNF-alpha, will potentiate ALA-PDT. We have the following specific aims: Aim 1 -Examine the effect of irradiance on PpIX photobleaching rates and normal tissue selectivity. This will occur in preclinical models and in patients. Aim 2 - Determine in patients the fluence-response relationships as a function of irradiance. Examine the effect on the host innate and adaptive immune responses. Aim 3 - Examine a rational combination therapy utilizing topical ALA-PDT and DMXAA in preclinical models and in patients.